This application is to request support for a Keystone Symposia meeting entitled RNA Silencing: Mechanism, Biology and Application, organized by Dr. Phillip D. Zamore and Dr. Beverly L. Davidson, which will be held in Keystone, CO from January 14 - 19, 2010. Since the discovery in 1993 of the first small silencing RNA, a dizzying number of small RNA classes have been identified, including microRNAs, various types of small interfering RNAs and piwi -interacting RNAs. These classes differ in their biogenesis, modes of target regulation, and in the biological pathways they regulate. However, there is also a growing realization that these distinct small RNA pathways are interconnected. These pathways function in developmental gene regulation, immunity, transcriptional silencing, and genomic stability. RNA silencing pathways function in RNA-based immunity, developmental gene regulation, transcriptional silencing, and genomic stability. The aim of this meeting is to explore the similarities and differences among RNA silencing pathways across the eukaryotic kingdom;to probe their underlying molecular mechanisms;to learn-by illustrative examples-the logic behind RNA-guided regulation of gene expression;as well as to explore new methods for harnessing these mechanisms for gene discovery and therapeutic applications. PUBLIC HEALTH RELEVANCE: RNA silencing pathways function in RNA-based immunity, developmental gene regulation, transcriptional silencing, and genomic stability. For instance, miRNAs play critical roles in virtually every biological pathway, although their roles in development and cancer have received special notice. The study of RNA silencing encompasses research in fungi, plants, basal eukaryotes, and animals. A key goal of The Keystone Symposia meeting on RNA Silencing: Mechanism, Biology and Application will be to highlight the unexpected, and often unexplained, complexity in the interactions among distinct small RNA pathways.